Salt taste plays an essential role in the detection of NaCI and other mineral salts and is part of the multi-organ regulatory system that maintains ion and water homeostasis. Understanding the nature of salt taste receptors and their regulation is important in the clinical management of diseases related to excess salt intake. There are two types of salt taste receptors, one that is sodium-specific and a second that does not discriminate among sodium, potassium, and ammonium ions. The apical amiloride-sensitive epithelial sodium channels constitute the sodium-specific salt taste receptor. One important and yet only partially answered question is: what is the molecular and biochemical identity of the second non-specific cation receptor? A major aim of this proposal is to identify natural and synthetic agonists and antagonists of this receptor channel that will reveal its biochemical identity. We have recently identified a pharmacological probe; cetylpyridinium chloride that depending upon its concentration acts as both an agonist and antagonist of this pathway and which suggests the receptor is a non-specific cation channel. We propose to characterize this pathway further by electrophysiological, pharmacological, and molecular methods. If this receptor channel is present in other tissues we will compare the properties of the receptor channel in taste receptor cells and in a tissue known to express it. Additional important areas in which we have significant gaps in our understanding are the mechanisms involved in the regulation of salt taste. Accordingly we will investigate how changes in cAMP, pH, calcium, and temperature regulate these two receptor-channels. We will utilize chorda tympani and glossopharyngeal taste nerve recordings with the lingual receptive field under voltage-clamp. These studies will be complemented by measuring changes in intracellular sodium, potassium, calcium, and pH activities in intact fungiform and circumvaliate papillae with epithelial tissue polarity preserved under voltage-clamp conditions. The identification of natural and synthetic analogues similar to cetylpyridinium chloride that modulate the non-specific cation receptor channel may be potentially useful as salt taste enhancers or suppressers.